Obesity is the most common nutritional disorder in the United States and, in adults, the reduction in lifespan associated with obesity can be attributed to the development of Type II diabetes mellitus as well as cardiovascular disorders including stroke, hypertension and heart disease. Advances in our understanding of underlying mechanisms that can cause energy imbalances have been aided by studies that focus on both the adipocyte and the brain. The recent discovery that disruption of melanocortin signaling in the CNS is the cause of obesity in the yellow obese mouse has led to the verification of a similar pathway that exists in humans, as well as the identification of mutations in the melanocortin 4 receptor (MC4-R) and proopiomelanocortin (POMC) genes causing human disease. In the CNS, neurons that express melanocortin receptors (MC4-R and/or MC3-R) are regulated by separate and independent populations of neurons originating in the arcuate nucleus of the hypothalamus (ARC), which express precursors for either a melanocortin agonist (POMC) or a naturally occurring antagonist (agouti-related protein or AGRP). Both POMC and AGRP neurons express receptors for leptin. While MC4-R deficient animals recapitulate agouti-induced obesity syndrome, little is known about the neuroendocrine circuits involved with melanocortin control of energy balance through this receptor. Since melanocortin receptors are expressed throughout the CNS, the immediate goals of this project are to test the overall hypothesis that hypothalamic and not brainstem expression of MC4-R governs melanocortin control of energy balance, and the specific hypotheses that expression of MC4-R in hypothalamic thyrotropin-releasing hormone (TRH) and melanin-concentrating hormone (MCH) neurons is required for normal weight homeostasis. Conditions for optimal regulation of CNS transgene expression in adult mice using an adenovirus and cre/lox technology will also be established. However, the long-term goal of this proposal is to develop animal models to define the neural circuitry by which a-MSH, AGRP, and CNS melanocortin receptors regulate feeding behaviour, thermogenesis, and cardiovascular control. To this end, MC4-R expression in the CNS will be modulated using cre recombinase.